Pd-Catalyzed Cyanation

Although cyanide is necessary for the cyanation reaction, it also plays the role of an inhibitor in the catalytic reaction due to its tendency to coordinate to the Pd or Pd species, besides the role of an indispensable reaction component. In general, metal cyanides only partially dissolve in the organic solvent. However, free cyanide can deactivate Pd complexes to a significant extent. Therefore, in order to provide an efficient catalytic reaction, the cyanide concentration must be low or in the same order of magnitude as the catalyst metal concentration. 

3 The Current Scope of the Pd-or Ni-Cata/yzed Cross-coupling 233 Me 

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A heterogeneous variant of the rapid microwave assisted homogeneous Pd-catalyzed cyanation process of Alterman and Hallberg was developed by Srivastava and Collibee (Schemes 67 and 68) [80]. The heterogeneous cat-... 

For Negishi reactions in which the pyridines are nucleophiles, the pyridylzinc reagents are usually prepared from the corresponding halopyridines [6, 20, 21]. An excess of 2-chlorozincpyridine /V-oxide (26), arising from 2-bromopyridine N-oxide hydrochloride (25), was coupled with vinyl triflate 27 in the presence of Pd(Ph3p)4 to furnish adduct 28 [20]. Recently, an efficient Pd-catalyzed cyanation of 2-amino-5-bromo-6-methylpyridine (29) using zinc cyanide has been reported to afford pyridyl nitrile 30 [22]. 

Pd-catalyzed cyanation of 2-methylpyrido[3,4- ]pyrazine 95 with Zn(CN)2 in the presence of Pd2(dba)3 and dppf gave the 5-cyano derivative 96 (dba = dibenzylideneacetone). Amination, without using any base, with benzylamine converted 95 into adduct 97 in excellent yield. Hydrolysis of 95 in aqueous formic acid provided the 5-oxo derivative 98 (Scheme 4) <2003H(60)925>. 

SCHEME 83. Pd-catalyzed cyanation of aryl electrophiles with Zn(CN)2... 

Sundermeier, M. Zapf, A. Beller, M. A convenient procedure for the Pd-catalyzed cyanation of aryl halides. Angew. Chem. Int. Ed. 2003, 42, 1661-1664. 

The palladium-catalyzed, microwave-assisted conversion of 3-bromopyridine to 3-cyanopyridine using zinc cyanide in dimethylformamide (DMF) has been reported <2000JOC7984>. Substoichiometric quantities of copper or zinc species improve both conversion rate and efficiency of Pd-catalyzed cyanation reactions <1998JOC8224>. A modification of this procedure uses a heterogeneous catalyst prepared from a polymer-supported triphenylphosphine resin and Pd(OAc)2 the nitriles were obtained from halopyridines in high yields <2004TL8895>. The successful cyanation of 3-chloropyridine is observed with potassium cyanide in the presence of palladium catalysts and tetramethylethylenediamine (TMEDA) as a co-catalyst <2001TL6707>. 

Me3SiCN is a convenient, reactive cyanide donor in transition metal-catalyzed processes. The Pd-catalyzed reaction of aryl iodides with Me3SiCN is useful for the synthesis of aryl cyanides.257 Me3SiCN works also as an effective co-catalyst for the Pd-catalyzed cyanation of aryl iodides with KCN.258 Allylic acetates, carbonates, and the related compounds undergo the Pd-catalyzed cyanation with Me3SiCN.259-261 The tandem cyclization-cyanation reaction of 2-bromo-l,6-heptadienes with Me3SiCN proceeds under catalysis by an Ni complex (Equation (68)).262... 

Aryl cyanides can be synthesized by Pd-catalyzed cyanation of halides or pseudohalides with Zn(CN)2- As an example, the triflate group in the pyrimidone 54 was displaced with CN group to afford 55 in high yield [62]. 

The order of reactivity of the aryl electrophiles in Pd-catalyzed cyanation is as follows aryl iodides > aryl triflates > aryl bromides > aryl chlorides. The lower the reactivity of the... 

TABLE 1. Pd-catalyzed Cyanation of Halobenzenes and Phenyl Ttiflate... 

Second, the addition of a catalytic amount of second metal salts, especially Cul, to the reaction mixture accelerates the Pd°-catalyzed cyanation.t t f Nitrile solvents are the best reaction media for the Cu+ cocatalyzed processes (Scheme 22). The activating effect of Cu is attributed to the role of vehicle transferring the CN between the poorly soluble cyanide source and the Pd intermediate. The same role exerted by the Pd species is also proposed for the Pd°-catalyzed reaction, CuCN itself is an effective source of cyanide (Scheme 23). ... 

In contrast to traditional methods for preparing nitriles such as the Sandmeyer [12] and Rosenmund-von Braun [13] reactions, the Pd-catalyzed cyanation provides an opportunity to convert an aryl halide or pseudohalide to a nitrile under relatively mild conditions. 

It was known that CN poisoning of the catalyst could be a problem in Pd-catalyzed cyanations [16, 17]. If this was the reason behind the failed 5 g reaction, why had it not been a problem in the 200 mg reaction ... 

Several improved protocols for the reaction have been reported, where various additives have been shown to improve the robustness and scope [31-34], but they all rely on high temperatures. The current example still remains one of very few reported cases where a Pd-catalyzed cyanation has been run on a large scale at temperatures <70°C [17-19]. Especially in the pharmaceutical industiy where molecules tend to be heavily functionalized, the ability to run the reactimi at low... 

The exceptional strength of the metal-cyanide linkage makes it challenging to develop catalytic processes that involve excess CN" as reagent. The Pd-catalyzed cyanation of aryl halides discussed in Chapter 19 to form aryl nitriles initially suffered from the formation of catalytically inactive cyanide complexes containing multiple CN" ligands the reaction has been improved by the use of ZnfCN) or Kj[Fe(CN)J as the CN" source. ... 

A Pd-catalyzed cyanation procedure using aryl halides and potassium cyanide was reported in 1973 (Scheme 3.79) [258, 259]. Many studies investigated effective Pd catalysts, metal cyanides, solvents, or additives, intending to provide the efficient catalytic reactions of a variety of carbon electrophiles including aryl halides under rrald conditions. In addition to Zn(CN)2, KCN, and NaCN, several other cyanide sources including NaCN, K4[Fe(CN),5], cyanohydrines, and trimethylsilyl cyanide (TMSCN) have been shown to participate in Pd-catalyzed cyanations [258b]. 

Scheme 3.79 Pd-catalyzed cyanation of aryl halides with KCN in DMF [258, 259].

Ushkov, A. V. Grushin, V. V. Rational catalysis design on the basis of mechanistic understanding Highly efficent Pd-catalyzed cyanation of aryl bromides with NaCN in recyclable solvents. J. Am. Chem. Soc. 2011, 133, 10999-11005. 

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